Introduction: In January 2020, the coronavirus disease 2019 (COVID-19) outbreak in Italy necessitated rigorous application of more restrictive safety procedures in the management and treatment of patients with cancer to ensure patient and staff protection. Identification of respiratory syndrome coronavirus 2 (SARS-CoV-2) infection was a challenge during the pandemic owing to a large number of asymptomatic or mildly symptomatic patients. Methods: We report 5 patients with unknown SARS-CoV-2 infection undergoing positron emission tomography (PET)/computed tomography (CT) with radiopharmaceuticals targeting different tumor processes: ¹⁸F-FDG, ¹⁸F-choline (FCH), and ⁶⁸Ga-PSMA. Results: In all patients, PET/CT showed increased tracer uptake in the lungs corresponding to CT findings of SARS-CoV-2 pneumonia. Quantitative assessment of tracer uptake showed more elevated values for the glucose analogue ¹⁸F-FDG (mean SUVmax 5.4) than for the other tracers (mean SUVmax 3.5). Conclusions: Our findings suggest that PET/CT is a sensitive modality to hypothesize SARS-CoV-2 pneumonia in patients with cancer, even when asymptomatic. More data are needed to verify the correlation among immune response to SARS-CoV-2 infection, clinical evolution, and PET results. Under the strict safety measures implemented at the PET center, the number of potentially SARS-CoV-2–positive patients undergoing PET/CT was very low (1.6%), and no staff member has been diagnosed with infection as of April 30, 2020.

Background: Prostate-specific membrane antigen (PSMA) has gained high attention as a useful biomarker in the imaging evaluation of prostate cancer with positron emission tomography (PET) during recent years. [⁶⁸Ga]-labeled Glu-urea-Lys(Ahx)-HBED-CC ([⁶⁸Ga]-PSMA-HBED-CC) is a novel PSMA inhibitor radiotracer which has demonstrated its suitability in detecting prostate cancer. Preparation conditions may influence the quality and in vivo behavior of this tracer, and no standard procedure for the quality control (QC) is available. The aim of this study was to develop a new rapid and simple high-pressure liquid chromatography method of analysis for the routine QCs of [⁶⁸Ga]-PSMA-HBED-CC to guarantee the high quality of the radiopharmaceutical product before release. Methods: A stepwise approach was used based on the quality by design concept of the International Conference of Harmonisation Q2 (R1) and Q8 (Pharmaceutical Development) guidelines in accordance with the regulations and requirements of European Association of Nuclear Medicine, Society of Nuclear Medicine, International Atomic Energy Agency, World Health Organization, and Italian Association of Nuclear Medicine and Molecular Imaging. The developed analytical test method was validated because a specific monograph in the pharmacopoeia is not available for [⁶⁸Ga]-PSMA-HBED-CC. Results: The purity and quality of the radiopharmaceutical obtained according to the proposed method resulted high enough to safely administrate it to patients. An excellent linearity was found between 0.8 and 5 μg/mL, with a detection limit of 0.2 μg/mL. Assay imprecision (% CV) was <2%. Conclusions: The developed method to assess the radiochemical and chemical purity of [⁶⁸Ga]-PSMA-HBED-CC is rapid, accurate, and reproducible, allowing routinely the use of this PET tracer as a diagnostic tool for imaging prostate cancer and also assuring patient safety.

Background: Glucagon-like peptide 1 receptor (GLP-1R) is preferentially expressed in pancreatic islets, especially in β-cells, and highly expressed in human insulinomas and gastrinomas. In recent years several GLP-1R–avid radioligands have been developed to image insulin-secreting tumors or to provide a tentative quantitative in vivo biomarker of pancreatic β-cell mass. Exendin-4, a 39-amino acid peptide with high binding affinity to GLP-1R, has been labeled with Ga-68 for imaging with positron emission tomography (PET). Preparation conditions may influence the quality and in vivo behavior of tracers. Starting from a published synthesis and quality controls (QCs) procedure, we have developed and validated a new rapid and simple UV-Radio-HPLC method to test the chemical and radiochemical purity of [⁶⁸Ga]Ga-NODAGA-exendin-4, to be used in the clinical routine. Methods: Ga-68 was obtained from a ⁶⁸Ge/⁶⁸Ga Generator (GalliaPharma^®) and purified using a cationic-exchange cartridge on an automated synthesis module (Scintomics GRP^®). NODAGA-exendin-4 contained in the reactor (10 µg) was reconstituted with HEPES and ascorbic acid. The reaction mixture was incubated at 100 °C. The product was purified through HLB cartridge, diluted, and sterilized. To validate the proposed UV-Radio-HPLC method, a stepwise approach was used, as defined in the guidance document released by the International Conference on Harmonization of Technical Requirements of Pharmaceuticals for Human Use (ICH), adopted by the European Medicines Agency (CMP/ICH/381/95 2014). The assessed parameters are specificity, linearity, precision (repeatability), accuracy, and limit of quantification. Therefore, a range of concentrations of Ga-NODAGA-exendin-4, NODAGA-exendin-4 (5, 4, 3.125, 1.25, 1, and 0.75 μg/mL) and [⁶⁸Ga]Ga-NODAGA-exendin-4 were analyzed. To validate the entire production process, three consecutive batches of [⁶⁸Ga]Ga-NODAGA-exendin-4 were tested. Results: Excellent linearity was found between 5–0.75 μg/mL for both the analytes (NODAGA-exendin-4 and ⁶⁸Ga-NODAGA-exendin-4), with a correlation coefficient (R²) for calibration curves equal to 0.999, average coefficients of variation (CV%) < 2% (0.45% and 0.39%) and average per cent deviation value of bias from 100%, of 0.06% and 0.04%, respectively. The calibration curve for the determination of [⁶⁸Ga]Ga-NODAGA-exendin-4 was linear with a R² of 0.993 and CV% < 2% (1.97%), in accordance to acceptance criteria. The intra-day and inter-day precision of our method was statistically confirmed using 10 μg of peptide. The mean radiochemical yield was 45 ± 2.4% in all the three validation batches of [⁶⁸Ga]Ga-NODAGA-exendin-4. The radiochemical purity of [⁶⁸Ga]Ga-NODAGA-exendin-4 was >95% (97.05%, 95.75% and 96.15%) in all the three batches. Conclusions: The developed UV-Radio-HPLC method to assess the radiochemical and chemical purity of [⁶⁸Ga]Ga-NODAGA-exendin-4 is rapid, accurate and reproducible like its fully automated production. It allows the routine use of this PET tracer as a diagnostic tool for PET imaging of GLP-1R expression in vivo, ensuring patient safety.

Background: Glucagon-like peptide 1 receptor (GLP-1R) is preferentially expressed in β-cells, but it is highly expressed in human insulinomas and gastrinomas. Several GLP-1 receptor–avid radioligands have been developed to image insulin-secreting tumors or to provide a quantitative in vivo biomarker of pancreatic β-cell mass. Exendin-4 is a high affinity ligand of the GLP1-R, which is a candidate for being labeled with a PET isotope and used for imaging purposes. Objective: Here, we report the development and validation results of a semi manual procedure to label [Lys40,Nle14(Ahx-NODAGA)NH2]exendin-4, with Ga-68. Methods: A ⁶⁸Ge/⁶⁸Ga Generator (GalliaPharma®,Eckert and Ziegler) was eluted with 0.1M HCl on an automated synthesis module (Scintomics GRP®). The peptide contained in the kit vial (Radioisotope Center POLATOM) in different amounts (10-20-30 µg) was reconstituted with 2-[4-(2-hydroxyethyl)piperazin-1-yl]ethansulfonic acid (HEPES) solution and 68GaCl3 (400–900 MBq), followed by 10 min incubation at 95°C. The reaction solution was then purified through an Oasis HLB column. The radiopharmaceutical product was tested for quality controls (CQs), in accordance with the European Pharmacopoeia standards. Results: The synthesis of ⁶⁸Ga]Ga-NODAGA-Exendin-4 provided optimal results with 10 µg of peptide, getting the best radiochemical yield (23.53 ± 2.4 %), molar activity (100 GBq/µmol) and radiochemical purity (91.69 %). Conclusion: The study developed an imaging tool [⁶⁸Ga]Ga-NODAGA-Exendin-4, avoiding pharmacological effects of exendin-4, for the clinical community.

Background: Gallium-68 is a positron emitter for PET applications that can be produced without cyclotron by a germanium (Ge-68) chloride/gallium (Ga-68) chloride generator. Short half-life (67.71 min) of Ga-68, matching pharmacokinetic properties of small biomolecules, facilitates isotope utilization in compounding radiopharmaceuticals for PET imaging. The increasing cost of good manufacturing practice-compliant generators has strengthened the need for radionuclide efficient use by planning specific radiopharmaceutical sessions during the week, careful maintenance of the generator and achievement of high labeling yield and radiochemical purity (RCP) of the radiolabeled molecules. Methods: The aim of this study was to evaluate the annual performance of five consecutive ⁶⁸Ge/⁶⁸Ga generators used for small-scale preparations of 68Ga-radiopharmaceuticals. To assess the long-term efficiency of isotope production we measured the weekly elution yield. To assess process efficiency we measured elution yield, labeling yield and RCP of four radiopharmaceutical preparations (⁶⁸Ga-DOTATOC, ⁶⁸Ga-PSMA-HBED-CC, ⁶⁸Ga-PENTIXAFOR and ⁶⁸Ga-DOTATATE). Results: The annual mean elution yield of the generators was 74.7%, higher than that indicated by the manufacturer, and it never went below 65%. The Ge-68 level in the final products was under the detection limits in all the produced batches (mean value 0.0000048%). The RCP of radiopharmaceuticals determined by high-performance liquid chromatography was 98 ± 0.22%. The mean yield of radiolabelling was 64.68, 68.71, 57 and 63.68% for ⁶⁸Ga-DOTATOC, ⁶⁸Ga-PSMA-HBED-CC, ⁶⁸GaPENTIXAFOR and ⁶⁸Ga-DOTATATE. Conclusion: The ability to prepare in the hospital radiopharmacy high-purity and pharmaceutically acceptable ⁶⁸Ga-radiolabeled probes on a routine basis facilitates patient access to precision imaging for clinical and research aims.

Purpose of the Study: Gallium (Ga)-68-DOTA peptides targeting somatostatin receptors have been assessed as a valuable tool in neuroendocrine tumor imaging using positron emission tomography. However, at the moment, a specific monograph in the European Pharmacopoeia (Ph. Eur.) does exist only for Ga-68-edotreotide (DOTATOC) injection. Here, we report on the validation process of Ga-68-DOTA-Tyr3-octreotate (DOTATATE) cassette-based production and quality control (QC). Materials and Methods: Preparation of Ga-68-DOTATATE was performed according to the current European Union-good manufacturing practices, the current good radiopharmacy practice, the Ph. Eur., and the guidelines on validation of analytical methods for radiopharmaceuticals. Process was validated via three consecutive production runs to ensure that the methods are reproducible and reliable in routine use. The QC tests for Ga-68-DOTATATE were radiochemical purity (RCP – high-pressure liquid chromatography [HPLC]), radiochemical impurities ⁶⁸Ga³⁺ (HPLC and instant thin layer chromatography [ITLC]), chemical purity (HPLC and gas chromatography [GC]), pH (pH-strips), radionuclidic purity (principal γ-photon), germanium-breakthrough (⁶⁸Ge-content), Ga-68 half-life (γ-ray spectrometry), and sterility/endotoxin assay. Results: Radiolabeling procedure of Ga-68-DOTATATE fits all the applicable Ph. Eur. specifications. RCP measured via ITLC was >99% in the three validation batches. HPLC-measured RCP resulted 99.45%, 99.78%, and 99.75%. Germanium-breakthrough was far below the recommended level established in the Ph. Eur. Ga-68-DOTATOC injection (#2482). Residual ethanol tested with GC was less than 10%. All the batches were tested for endotoxin content, which always resulted lower than 17.5 EU/ml. All preparations passed the sterility tests. pH of the final product was 7 in all samples. Conclusion: Ga-68-DOTATATE fulfilled all the pre-set QCs and release criteria in the batches considered for this validation study. The results demonstrated a batch-to-batch reproducibility, ensuring that synthesis process leads to the expected final product in terms of yield, quality, reliability, safety, and efficacy.